Viral adaptations to alternative hosts in the honey bee pathogen .

Bacteriophages (phages) that are intended to be used to treat bacterial infections are often improved using genetic engineering or experimental evolution. A protocol called "Appelmans" utilizes evolution in microtiter plates to promote the evolution of phages that can infect nonpermissive hosts. We tested a modification of the Appelmans protocol using the honey bee pathogen, .

Bacteriophage resistance evolution in a honey bee pathogen.

Honey bee () larvae are susceptible to the bacterial pathogen , which causes severe damage to bee colonies. Antibiotic treatment requires veterinary supervision in the United States, is not used in many parts of the world, perpetuates problems associated with antibiotic resistance, and can necessitate residual testing in bee products. There is interest in using bacteriophages to treat infected colonies (bacteriophage therapy) and several trials are promising.

Comparison of Characteristics of Deaths From Drug Overdose Before vs During the COVID-19 Pandemic in Rhode Island.

Importance: The rate of deaths from overdose has increased during the COVID-19 pandemic, and recent US overdose mortality rates have been markedly high. However, scant data are available on the causes of this increase or subpopulations at elevated risk.

Objective: To evaluate the rates and characteristics of deaths from drug overdose before vs during the COVID-19 pandemic.

Predictors of enrollment in opioid agonist therapy after opioid overdose or diagnosis with opioid use disorder: A cohort study.

Background: Medicaid recipients have a high burden of opioid overdose and opioid use disorder (OUD). Opioid agonist therapies are an effective treatment for OUD, but there is a wide and persisting gap between those who are indicated and those who receive treatment. The objective of this study was to identify the predictors of enrollment in opioid agonist therapy within 6 months of an opioid overdose or OUD diagnosis in a cohort of Medicaid recipients.

Lung mechanical properties distinguish children with asthma with normal and diminished lung function.

Background: Children with asthma, even those with severe persistent disease, can have forced expiratory volume in 1 second (FEV ) values ≥100% of predicted, while others have diminished FEV .

Objective: We sought to characterize the lung mechanical properties underlying these two asthma phenotypes and the mechanisms explaining the paradox of severe asthmatic children, whom when clinically stable can have an FEV >100% of predicted, but during an acute bronchospastic episode can experience a life-threatening asthma event.

Methods: Lung mechanics were evaluated in three groups of children: asthmatics with FEV ≥100% (HFEV ; n = 13), asthmatics with FEV ≤80% (LFEV ; n = 14) and non-asthmatic controls (n = 10).

Defining a recovery-oriented cascade of care for opioid use disorder: A community-driven, statewide cross-sectional assessment.

Background: In light of the accelerating and rapidly evolving overdose crisis in the United States (US), new strategies are needed to address the epidemic and to efficiently engage and retain individuals in care for opioid use disorder (OUD). Moreover, there is an increasing need for novel approaches to using health data to identify gaps in the cascade of care for persons with OUD.

Methods And Findings: Between June 2018 and May 2019, we engaged a diverse stakeholder group (including directors of statewide health and social service agencies) to develop a statewide, patient-centered cascade of care for OUD for Rhode Island, a small state in New England, a region highly impacted by the opioid crisis.

Spoiled milk: an experimental examination of bias against mothers who breastfeed.

Drawing from the objectification literature, three experiments tested the hypothesis that breastfeeding mothers are the victims of bias. In Study 1, participants rated a woman who had breastfed as incompetent. Study 2 replicated these effects and determined that the bias was specific to conditions that sexualized the breast.

Do NHLBI lung function criteria apply to children? A cross-sectional evaluation of childhood asthma at National Jewish Medical and Research Center, 1999-2002.

Although National Heart Lung Institute (NHLBI) guidelines categorize asthma severity based on spirometry, few studies have evaluated the utility of these spirometric values in grading asthma severity in children. Asthma is thought to be progressive, but little is known about the loss of lung function in childhood. This study sought to determine the spirometric indices in children from 4-18 years of age.

Identification and proposed mechanism of action of thymidine kinase inhibition associated with cellular exposure to camptothecin analogs.

Purpose: To investigate the effects of several camptothecin analogs including 9-aminocamptothecin (9-AC), SN38, topotecan, and irinotecan (CPT-11) on the enzymes involved in the pyrimidine salvage pathway including thymidylate synthase (TS). A COMPARE analysis using the NCI 60 cell line drug-screening panel suggested that there were similarities in the mechanisms of action of camptothecin analogs and TS inhibitors.

Methods: TS enzymatic activity was measured by both an in situ tritium release assay using both the H630 colon cancer cell line and the CEM human leukemia cell line, and by a radiolabelled in vitro assay using partially purified human TS as the enzyme source.

Mining and visualizing large anticancer drug discovery databases.

In order to find more effective anticancer drugs, the U.S. National Cancer Institute (NCI) screens a large number of compounds in vitro against 60 human cancer cell lines from different organs of origin.

The ras oncogene-mediated sensitization of human cells to topoisomerase II inhibitor-induced apoptosis.

Background: Among the inhibitors of the enzyme topoisomerase II (an important target for chemotherapeutic drugs) tested in the National Cancer Institute's In Vitro Antineoplastic Drug Screen, NSC 284682 (3'-hydroxydaunorubicin) and NSC 659687 [9-hydroxy-5,6-dimethyl-1-(N-[2(dimethylamino)ethyl]carbamoyl)-6H-pyrido -(4,3-b)carbazole] were the only compounds that were more cytotoxic to tumor cells harboring an activated ras oncogene than to tumor cells bearing wild-type ras alleles. Expression of the multidrug resistance proteins P-glycoprotein and MRP (multidrug resistance-associated protein) facilitates tumor cell resistance to topoisomerase II inhibitors. We investigated whether tumor cells with activated ras oncogenes showed enhanced sensitivity to other topoisomerase II inhibitors in the absence of the multidrug-resistant phenotype.

Synthesis of cytotoxic indenoisoquinoline topoisomerase I poisons.

A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity vs topoisomerase 1 (top1). The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (21) and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (22), both of which displayed submicromolar mean graph midpoints when tested in 55 human cancer cell cultures. Two of the most potent top1 inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5, 11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2, 3-dimethoxy-8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinolinium chloride (27), both of which also inhibited top2, unwound DNA, and are assumed to be DNA intercalators.

Using the national cancer institute anticancer drug screen to assess the effect of MRP expression on drug sensitivity profiles.

The MRP gene contributes to one form of multidrug resistance. To identify drugs interacting with MRP, we measured MRP mRNA expression by quantitative PCR in 60 cell lines of the National Cancer Institute Anticancer Drug Screen. Expression was detected in all cell lines (highest in lung carcinomas and central nervous system tumors) with a range of 14-fold.

Influence of 2-(4-aminophenyl)benzothiazoles on growth of human ovarian carcinoma cells in vitro and in vivo.

2-(4-Aminophenyl)benzothiazole molecules substituted in the 3 position of the phenyl ring with a halogen atom or methyl moiety comprise a group of compounds that potently inhibit specific human ovarian carcinoma cell lines. GI50 values fall within the nM range. Inhibition is highly selective -- whereas the GI50 value in IGROV1 cells consistently lies at < 10 nM, SK-OV-3 presents GI50 values > 10 microM.

Protein-linked DNA strand breaks induced by NSC 314622, a novel noncamptothecin topoisomerase I poison.

NSC 314622 was found to have a cytotoxicity profile comparable to the topoisomerase I (top1) inhibitors camptothecin (CPT) and saintopin in the National Cancer Institute In Vitro Anticancer Drug Discovery Screen using the COMPARE analysis. In vitro data showed that NSC 314622 induced DNA cleavage in the presence of top1 at micromolar concentrations. Cleavage specificity was different from CPT in that NSC 314622 did not cleave all sites induced by CPT whereas some sites were unique to the NSC 314622 treatment.

Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor.

Anthrax lethal toxin, produced by the bacterium Bacillus anthracis, is the major cause of death in animals infected with anthrax. One component of this toxin, lethal factor (LF), is suspected to be a metalloprotease, but no physiological substrates have been identified. Here it is shown that LF is a protease that cleaves the amino terminus of mitogen-activated protein kinase kinases 1 and 2 (MAPKK1 and MAPKK2) and that this cleavage inactivates MAPKK1 and inhibits the MAPK signal transduction pathway.

Mining the NCI anticancer drug discovery databases: genetic function approximation for the QSAR study of anticancer ellipticine analogues.

The U.S. National Cancer Institute (NCI) conducts a drug discovery program in which approximately 10,000 compounds are screened every year in vitro against a panel of 60 human cancer cell lines from different organs of origin.

2-(4-Aminophenyl)benzothiazoles: novel agents with selective profiles of in vitro anti-tumour activity.

2-(4-Aminophenyl)benzothiazole (CJM 126) elicits biphasic growth-inhibitory effects against a panel of oestrogen receptor-positive (ER+) and oestrogen receptor-negative (ER-) human mammary carcinoma cell lines in vitro, yielding IC50 values in the nM range. Substitutions adjacent to the amino group in the 2-phenyl ring with a halogen atom or methyl group enhance potency in sensitive breast lines (pM IC50 values). Transient biphasic dose responses were induced but rapidly eradicated after specific drug exposure periods.

Mining the National Cancer Institute Anticancer Drug Discovery Database: cluster analysis of ellipticine analogs with p53-inverse and central nervous system-selective patterns of activity.

The United States National Cancer Institute conducts an anticancer drug discovery program in which approximately 10,000 compounds are screened every year in vitro against a panel of 60 human cancer cell lines from different organs. To date, approximately 62,000 compounds have been tested in the program, and a large amount of information on their activity patterns has been accumulated. For the current study, anticancer activity patterns of 112 ellipticine analogs were analyzed with the use of a hierarchical clustering algorithm.

Identification of epidermal growth factor receptor and c-erbB2 pathway inhibitors by correlation with gene expression patterns.

Background: Growth factor receptor-signaling pathways are potentially important targets for anticancer therapy. The interaction of anticancer agents with specific molecular targets can be identified by correlating target expression patterns with cytotoxicity patterns. We sought to identify new agents that target and inhibit the activity of the epidermal growth factor (EGF) receptor and of c-erbB2 (also called HER2 or neu), by correlating EGF receptor, transforming growth factor (TGF)-alpha (a ligand for EGF receptor), and c-erbB2 messenger RNA (mRNA) expression levels with the results of cytotoxicity assays of the 49000 compounds in the National Cancer Institute (NCI) drug screen database.

Reduced folate carrier gene (RFC1) expression and anti-folate resistance in transfected and non-selected cell lines.

Methotrexate transport deficiency due to decreased reduced folate carrier (RFC) activity has been observed in several cell lines selected for resistance to methotrexate (MTX). Since MTX resistance is multifactorial, however, it is difficult to quantify the relative importance of changes in RFC activity in selected cell lines and even more so to determine the relative contribution of naturally occurring RFC activity in the MTX sensitivity of non-selected cell lines. We examined the role of RFC in MTX resistance by studying a transport-deficient cell line transfected with the gene for human RFC, RFC1, and by correlating relative RFC1 expression with MTX and trimetrexate (TMTX) growth inhibition (GI50) in a panel of cell lines used in the NCI Anticancer Drug Screen.

P-glycoprotein substrates and antagonists cluster into two distinct groups.

To gather further insight into the interaction between P-glycoprotein (Pgp) and its substrates, 167 compounds were analyzed in multidrug resistant human colon carcinoma cells. These compounds were selected from the National Cancer Institute Drug Screen repository using computer-generated correlations with known Pgp substrates and antagonists. The compounds were prospectively defined as Pgp substrates if cytotoxicity was increased > or =4-fold by the addition of cyclosporin A (CsA) and as Pgp antagonists if inhibition of efflux increased rhodamine accumulation by 4-fold.

Identification of compounds with preferential inhibitory activity against low-Nm23-expressing human breast carcinoma and melanoma cell lines.

We have used the COMPARE computer algorithm and Nm23 expression as a marker of tumor metastatic potential to examine the in vitro antiproliferative activity of chemotherapeutic drugs on human breast carcinoma and melanoma cell lines. None of 171 compounds in clinical use or under development and only 40 of 30,000 repository compounds exhibited preferential growth inhibition of low-Nm23-expressing, metastatically aggressive cell lines with a Pearson correlation coefficient of < or = -0.64.